Henry R. Black, MD: Hi. I'm Dr. Henry Black. I'm Clinical Professor of Internal Medicine at the New York University School of Medicine, a member of the Center for the Prevention of Cardiovascular Disease, and Immediate Past President of the American Society of Hypertension. I'm here with my friend and colleague, Dr. Jonathan Halperin.
Jonathan L. Halperin, MD: Hi. I'm Jon Halperin, a cardiologist and Professor of Medicine at Mount Sinai School of Medicine in New York City.
Dr. Black: Jon, one of the things I wanted to talk about is that from my perspective, someone who is not a cardiologist and doesn't treat people who need secondary prevention, there seems to be an enormous number of new approaches to platelet inhibition and anticoagulation. We are beyond aspirin, warfarin, and clopidogrel now. How do you sort these out?
Dr. Halperin: I think you've made the key distinction, Henry, which is platelet inhibitors vs anticoagulants. Platelet inhibitors are the predominant approach to patients with arterial obstructive disease, atherosclerosis, and particularly acute coronary syndromes. For years, we have relied upon heparin as the initial approach. Then we added aspirin and, ultimately, clopidogrel, continuing dual antiplatelet therapy, particularly for patients who undergo a percutaneous coronary intervention. Over time, we generally moved back toward antiplatelet monotherapy.
As you know, clopidogrel is going to become a generically available compound this month in the United States. Just when this transition is occurring, 2 agents have arrived that have been shown to be superior to clopidogrel in the management of patients with acute coronary syndromes. The first is prasugrel and the second is ticagrelor. Each drug was tested against clopidogrel in conjunction with aspirin in patients with acute coronary syndromes.[1-3] Each drug was more effective in preventing myocardial infarction and ultimately showed a reduction in mortality. How rapidly these agents will be taken up by practitioners remains to be seen, because the price of clopidogrel is likely to drop as a generic compound.
Dr. Black: Weren't there concerns about some of the subgroups in those studies?
Dr. Halperin: Yes. In the trials with prasugrel,[1,3] there were concerns about an increased risk for stroke, particularly hemorrhagic stroke, in patients who received prasugrel compared with those who received clopidogrel and aspirin. It was not as apparent with ticagrelor. There was also an advantage in overall mortality. Because of the shorter duration of action of ticagrelor, there are some advantages in patients who, for example, require urgent cardiac bypass surgery. Both are classified as P2Y12 inhibitors, moving from the thienopyridine group into more selective compounds. These drugs will be important advances for some patients, but how to select patients for these new agents remains a bit uncertain. Price will certainly play a role in the marketplace.
Dr. Black: I have some patients that I'm seeing for hypertension or hyperlipidemia who have been on clopidogrel for a year. The current recommendations are that you stop taking it at 1 year, but it's hard for me to have them stop if their cardiologist doesn't want them to. What is your approach to that?
Dr. Halperin: I think we should look back to one of the earliest trials. The CAPRIE trial[4] was conducted in patients who had a history of myocardial infarction, non-disabling stroke, or peripheral arterial disease. They were randomly assigned to receive either aspirin or clopidogrel. Although the difference was relatively small, there was a significant overall advantage to clopidogrel. What I tend to do over time is favor clopidogrel therapy, particularly for patients who remain at elevated risk. The other agents that you mentioned were the anticoagulants. For over 50 years, we depended on warfarin as the only oral anticoagulant, a vitamin K antagonist. Every physician knows how difficult that drug can be for patients to sustain over time, with frequent drug and food interactions and the need for blood test monitoring to steer the ship between the shoals of not enough, where the risk for thrombosis rages, and too much, where the risk for hemorrhage prevails.
Now we have an emerging wealth of new agents. The first was dabigatran etexilate, an oral direct thrombin inhibitor. More recent are rivaroxaban and apixaban, factor Xa inhibitors. The broadest market for these agents is going to be patients with atrial fibrillation who face an increased risk for stroke over their lifetimes. For these patients, the new agents have real evidence of superiority in one unequivocal way: They dramatically reduce the risk for brain hemorrhage. Even though there is uncertainty about whether they are actually superior or simply noninferior to warfarin in preventing ischemic stroke and systemic embolism, they have all been shown to compare favorably with respect to overall bleeding and to dramatically reduce the risk for the worst complication of antithrombotic therapy, which is hemorrhage in the brain.
Dr. Black: The concern I have heard is that you can't reverse those if you need to, but you can with warfarin.
Dr. Halperin: Exactly. That is an interesting point. I think you are absolutely right. There are no antidotes available for any of these new oral anticoagulants. On the other hand, they have a relatively short duration of action, typically 12-24 hours, and the drugs are at least largely withdrawn from the circulation as far as an active anticoagulant is concerned. Although warfarin has antidotes in the form of vitamin K and fresh frozen plasma, it's not quite clear that when we correct the coagulation assay, we are actually reducing the patient's risk for bleeding. If a patient arrives in the emergency department while actively bleeding and we administer vitamin K, fresh frozen plasma, or prothrombin concentrate preparations to reverse the anticoagulant effect, the laboratory tests get better right away. But what about the patient's risk for bleeding and the ultimate outcome? It's not very clear that those are actually improved.
Dr. Black: What do you do if you are faced with someone on one of the newer agents who has a hemorrhage that you would like to reverse? Do you just have to wait it out?
Dr. Halperin: We don't know, to tell you the truth. There have been trials of various strategies. Administration of prothrombin complex concentrate has been shown in a very small study of normal individuals to seemingly reverse the effect of the factor Xa inhibitors, perhaps not so much the factor IIa inhibitor.[5] Whether they will translate into actual clinical outcome differences remains unclear. Overall support of the patient, hydration, and addressing the cause of the bleeding is very important.
It's important to know that with dabigatran, which is the factor IIa or thrombin inhibitor, the drug is dialyzable. It can be removed by that method. The price that we pay is that it is more dependent on renal function for excretion, so we have to be more cautious about using the drug when there is compromised renal function.
On the other hand, all of these drugs have the advantage of a relatively short half-life and they performed very favorably compared with warfarin, even very well-adjusted warfarin in randomized trials, with no increase in overall bleeding. They do have a tendency to cause more gastrointestinal bleeding, particularly dabigatran and rivaroxaban. Apixaban, which is not yet approved by the US Food and Drug Administration but is going for review in the near future and is expected to gain approval, did not show an increase in gastrointestinal bleeding. It significantly reduced major bleeding overall compared with warfarin.
It's important when we make comparisons, however, to recognize that these trials were all designed a little differently. Definitions of major bleeding were different. Even the definitions of the time and therapeutic range on warfarin were different. Therefore, we should always be very hesitant and cautious about cross-trial comparisons. It's particularly an important caution with respect to these new drugs.
Dr. Black: Don't you wish we could plan trials cooperatively and decide to use the same endpoints, the same timeframes, and the same patient populations? But that is probably not going to happen.
Dr. Halperin: Not likely to happen, in part because, with each trial, we learn from the ones before it and try to do a better job.
Dr. Black: Right. Thanks very much, Jonathan. That was very helpful.
Comments
Post a Comment